In recognition of hypoxia’s involvement in atherogenesis, it has been suggested that plaque hypoxia be used as a target for molecular imaging to identify high-risk patients, anticipate acute cardiovascular events, and monitor atheroma therapies (1). We demonstrate the potential of hypoxia imaging in humans using a highly selective hypoxia marker, 18F-2-(4-((2-nitro-1H-imidazol-1-yl)methyl)-1H-1,2,3-triazol-1-yl)propan-1-ol (HX4), for positron emission tomography/computed tomography (PET/CT) (2).

Patients included in this study were characterized by advanced atherosclerosis, as detected by the elevated normalized wall index (NWI) on magnetic resonance imaging (MRI) and elevated 18F-fluorodeoxyglucose (FDG) uptake in the arterial wall, expressed as the target-to-background ratio (TBR) in the index vessel measured with positron emission tomography/computed tomography (PET/CT). As a marker of hypoxia, 18F-2-(4-((2-nitro-1H-imidazol-1-yl)methyl)-1H-1,2,3-triazol-1-yl)propan-1-ol (HX4) uptake was enhanced in both the carotid arteries as the aorta, quantified as HX4 TBR using PET/CT (scale bars indicate 2 cm). A schematic of the analyzed segments with the corresponding MRI, CT, HX4-PET/CT, and FDG-PET/CT images in the most diseased area of the plaque compared to nonplaque regions underscore plaque-specific HX4 uptake in patients (scale bars indicate 1 cm).

Subsequently, HX4 uptake was assessed at the level of the carotid arteries in 4 patients and at the level of the aorta in the other 4 patients (Figure 1). When quantified, HX4TBRmax of the carotid arteries was 1.27 ± 0.13 and 1.98 ± 0.27 for the aorta (Figure 1). HX4 uptake was specific to plaque regions —HX4TBRmax was 1.32 ± 0.16 in the most diseased segment compared with 1.15 ± 0.20 in the nonplaque region (p < 0.01) (Figure 1). Following the relationship between plaque burden and hypoxia, we observed a strong correlation between atherosclerotic HX4 uptake and carotid arterial wall dimensions (r = 0.97; p = 0.04). In addition, we showed a correlation with HX4 uptake and FDG uptake in the plaque (r = 0.75; p = 0.03).

Taken together, we showed increased HX4 uptake in plaque regions that correlated to arterial wall dimensions and metabolic activity. Recently, a pre-clinical PET study in atherosclerotic rabbits showed positive correlations of the hypoxia tracer 18F-fluoromisonidazole to plaque burden and macrophage content, but not to FDG uptake, which might reflect distinct differences in rabbit and human plaque composition (4). In support, previous work in human carotid artery specimens showed in situ correlations between a nonradioactive structural analogue of HX4, pimonidazole, and features of plaque vulnerability (5). Nonetheless, additional studies are warranted to assess HX4’s relationship with FDG and its direct link to hypoxia-associated molecules in human plaques. Future studies are aimed at: 1) using additional MRI imaging sequences or MRI–traceable HX4 to overcome the low spatial resolution of PET and provide greater insight in HX4 uptake in different plaque components; and 2) addressing the relationship between HX4, hypoxia, and plaque vulnerability in vivo.

In conclusion, we present a noninvasive imaging approach to visualize hypoxia in advanced atherosclerotic lesions in humans in vivo. Current data support efforts to develop and implement imaging modalities to quantify hypoxia in patients at risk for cardiovascular disease.

Footnotes

Please note: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.